E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
chronic obstructive pulmonary disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
lung disease in which the lungs are damaged, making it hard to breathe. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate discontinuation rates of roflumilast 500μg OD using an up-titration regimen with either 250μg OD or 500μg EOD for the first 4 weeks of treatment followed by 500μg OD for 8 weeks compared with continuous treatment of 500μg OD during the entire 12-week main period.
To evaluate if subjects who do not tolerate roflumilast 500μg OD have a drug exposure with 250μg roflumilast OD similar to that observed in other subjects with the 500μg OD dose. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the gastro-intestinal tolerability of roflumilast 500μg OD with an up-titration regimen compared with continuous treatment of 500μg OD. To evaluate the safety, discontinuations and tolerability especially the gastro-intestinal tolerability of roflumilast 250μg OD in subjects not tolerating the 500μg OD dose. To evaluate the safety of roflumilast 500μg OD with an up-titration regimen compared with continuous treatment of 500μg OD. To evaluate the efficacy of roflumilast 500μg OD with an up-titration regimen on lung function compared with continuous treatment of 500μg OD.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements. 2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. The subject has a history of COPD (according to GOLD 2013[1]) for at least 12 months prior to Screening (Visit V0) associated with chronic productive cough for 3 months in each of the 2 years prior to Screening (Visit V0, with other causes of productive cough excluded). 4. The subject shows a post-bronchodilator FEV1 of ≤50% of predicted. 5. The subject shows an FEV1/forced vital capacity (FVC) ratio (post-bronchodilator) <70%. 6. The subject has at least one documented COPD exacerbation within one year prior to Screening (Visit V0). 7. The subject is on standard of care COPD maintenance treatment including LABAs, long acting anticholinergics, or any combination thereof taken on a constant daily dose within 12 weeks prior to Screening (Visit V0) 8. The subject must be a former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 10 pack years. 9. The subject is male or female and aged 40 or older. 10. A female subject of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to use routinely adequate contraception* from signing of informed consent throughout the duration of the study. |
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E.4 | Principal exclusion criteria |
1. The subject has a COPD exacerbation ongoing at the Screening (Visit V0), or has a COPD exacerbation between V0 and V1. 2. The subject has a lower respiratory tract infection not resolved 4 weeks prior to Screening (Visit V0). 3. The subject has a diagnosis of asthma and/or other relevant lung disease (eg, history of primary bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [eg, fibrosis, silicosis, sarcoidosis], or active tuberculosis). 4. The subject has a known α1-antitrypsin deficiency. 5. The subject has taken roflumilast within 6 months of Screening (Visit V0). Criteria within ethical considerations in terms of general health 6. The subject has clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the investigator). 7. The subject has a history of severe psychiatric or neurological disorders. 8. The subject has a history of depression associated with suicidal ideation or behavior. 9. The subject has congestive heart failure severity grade IV according to NYHA Functional Classification. 10. The subject has hemodynamically significant cardiac arrhythmias or heart valve deformations. 11. The subject has CT or chest x-ray findings indicating an acute pulmonary disease other than COPD (eg, tuberculosis, severe bronchiectasis, tumors). 12. The subject has severe immunological diseases (eg, known human immune deficiency virus (HIV) infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy). 13. The subject has liver impairment Child-Pugh B or C and/or active viral hepatitis. 14. The subject has severe acute infectious diseases (eg, tuberculosis, or acute hepatitis). 15. The subject has a history of malignant disease (except basal cell carcinoma) within 5 years before Screening (Visit V0). 16. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within one year before Screening (Visit V0). 17. The subject has a history of hypersensitivity or allergies to roflumilast or rescue medication or ingredients thereof, or any other contraindication for the use thereof. 18. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 12 weeks after participating in this study; or intending to donate ova during such time period. 19. The subject intends to donate blood, organs, or bone marrow during the course of the study. 20. The subject has received any investigational compound within 30 days prior to Screening (Visit V0), is currently participating in another interventional clinical study, or has been previously enrolled in this study. 21. The subject is suspected to be unable or unwilling to comply with study procedures (eg, language problems, psychological disorders, number and timing of visits at the center). 22. The subject suffers from any concomitant disease that might interfere with study procedures or evaluations. 23. The subject is required to take excluded medications (see Section 7.4). 24. The subject is an immediate family member, study center employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage of subjects prematurely discontinuing study treatment due to any reason (during main period ie, Visit V1 to Vend). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Percentage of subjects with adverse events of interest to evaluate tolerability - diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (main period, V1 to Vend) • Change in pre-bronchodilator FEV1 during the down-titration period, from V0DT to VendDT • Percentage of subjects prematurely discontinuing study treatment due to any reason (during down-titration period, V0DT to VendDT) Other secondary endpoints for this study are: • Change in pre-bronchodilator FVC and pre-bronchodilator FEV1 from V1 to V2, V3, V4 and Vend (during main period of the study) • To characterize the efficacy of roflumilast 250μg OD on lung function during a down-titration period, in subjects who do not tolerate roflumilast 500μg OD • Change in subject-assessed treatment satisfaction scores from V1 to V2, V3, V4 and Vend (during main period of the study) • To characterize subject-assessed treatment satisfaction of roflumilast 250μg OD during a down-titration period, in subjects who do not tolerate roflumilast 500μg OD. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
as shown in the list above, up to week 12 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
open-label in down titration period |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Lower dose of drug (250ug) and a different dosing regime of the 500 ug dose |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 126 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Korea, Republic of |
Philippines |
Russian Federation |
South Africa |
Thailand |
Ukraine |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end-of-trial is defined as database hard-lock, which will be subsequent to the follow-up visit of the last patient. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |